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Cycloserine rTMS Plasticity Augmentation

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ClinicalTrials.gov Identifier: NCT03432689
Recruitment Status : Completed
First Posted : February 14, 2018
Last Update Posted : November 9, 2018
Sponsor:
Information provided by (Responsible Party):
Alexander McGirr, University of Calgary

Study Description
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Brief Summary:
Transcranial magnetic stimulation (rTMS) is an investigational and therapeutic modality that impacts the connection strength between neurons by delivering patterned energy. In response to this patterned energy neurons fire and adapt by changing their connection strengths. This change in connection strengths is believed to be the underlying mechanism whereby this intervention has therapeutic benefit for this intervention in conditions such as depression. The purpose of this study is to test a means of enhancing the effect of rTMS using a medication (cycloserine) that has been shown to augment and stabilize activity dependent neuronal changes. The investigators wish to use the motor system, where the associated muscle response to brain stimulation can be measured, to probe activity dependent changes in connection strength between neurons.

Condition or disease Intervention/treatment Phase
Motor Activity Device: Transcranial Magnetic Stimulation Drug: Cycloserine Drug: Placebo Oral Tablet Phase 1

Detailed Description:

This randomized, placebo-controlled, crossover trial will enroll 12 healthy participants. In one arm of the study, participants will randomly receive either 100mg of d-cycloserine (DCS, an antibiotic) or a placebo capsule, and participants will receive the other intervention one week later.

  1. The investigators will recruit 12 healthy participants through community advertisement, carefully screened for exclusion factors related to rTMS and DCS.
  2. Participants will be randomly assigned by random number sequence with allocation concealment to one of two first arms of the crossover study: a) placebo-DCS 100mg and b) DCS 100mg-placebo.
  3. Participants will complete the QIDS-SR (Quick Inventory of Depressive Symptoms-Self Report), the MDQ (Mood Disorders Questionnaire), the BAI (Beck Anxiety Inventory), and the STAI (State Trait Anxiety Inventory).
  4. Participants will take their blinded capsule at least 30 minutes hours prior to TBS. (we anticipate that it will take approximately 30 minutes to do steps 5-7).
  5. Electromyographic (EMG) electrodes will be positioned over the first dorsal interosseous (FDI) bilaterally to record motor evoked potentials (MEPs). These are non-invasive electrodes that use an adhesive to stick to the skin.
  6. Using neuronavigation in conjunction with an atlas brain, the M1 hand strip will be localized using single pulse TMS (MagPro X100).
  7. Motor evoked potentials are measurements of muscle activation, in this case in response to TMS stimulation of the brain. The investigators will use single pulse TMS to record the magnitude of responses. As a baseline, the investigators will collect twenty single-pulse (120% resting motor threshold (RMT), 0.25Hz) MEPs every 5 minutes for the 15 minutes preceding TBS rTMS.
  8. TBS rTMS will be applied to the FDI 'hotspot'. TBS consists of 2s trains every 10s. Trains are composed of 3 pulses at 50Hz, 200ms intervals, 80% RMT. Total time 190s and 600 pulses.
  9. After TBS, twenty MEPs will be acquired (single pulse, 120% RMT, 0.25Hz) every 5 minutes for the first 30 minutes, at 60 minutes, at 90 minutes, and at 16Hrs (the following morning).
  10. At the 16 Hrs time point, the investigators will characterize stimulus response curves (MEPs at stimulus intensities ranging from 100-150% resting motor threshold presented in random order).

As this is a cross-over study, participants will return 1 week later to repeat the second arm of the protocol and will repeat steps 2-10).

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: A Randomized, Placebo-controlled, Crossover Trial of Cycloserine Repetitive Transcranial Magnetic Stimulation Plasticity Enhancement in the Healthy Motor System.
Actual Study Start Date : August 6, 2018
Actual Primary Completion Date : November 7, 2018
Actual Study Completion Date : November 7, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Cycloserine

Arms and Interventions
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Arm Intervention/treatment
Experimental: D-Cycloserine
Participants will ingest a capsule containing 100mg of the antibiotic d-cycloserine. Their baseline motor evoked potentials (MEP) will be recorded for 30 minutes prior to receiving theta-burst stimulation (TBS; a patterned stimulation) to the motor cortex and change in MEP amplitude will be measured following stimulation up to 90 minutes later and then once again the following morning (16 hours later).
 Device: Transcranial Magnetic Stimulation
Single-pulse transcranial magnetic stimulation and theta-burst stimulation

Drug: Cycloserine
Cycloserine 100mg
Placebo Comparator: Placebo
Participants will ingest a capsule identical to that containing the study medication, however this capsule will contain a placebo. Their baseline motor evoked potentials (MEP) will be recorded for 30 minutes prior to receiving theta-burst stimulation (TBS; a patterned stimulation) to the motor cortex and change in MEP amplitude will be measured following stimulation up to 90 minutes later and then once again the following morning (16 hours later).
 Device: Transcranial Magnetic Stimulation
Single-pulse transcranial magnetic stimulation and theta-burst stimulation

Drug: Placebo Oral Tablet
Placebo capsule matched to cycloserine capsule


Outcome Measures
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Primary Outcome Measures :
  1. Motor Evoked Potential amplitude [ Time Frame: Baseline versus 90 minutes following theta-burst stimulation. ]
    Change in the (electrical) amplitude of muscle responses to stimulation of the motor cortex will be recorded from the first dorsal interosseous muscle of the hand.


Secondary Outcome Measures :
  1. Motor Evoked Potential dose-response curve [ Time Frame: Baseline versus 90 minutes following theta-burst stimulation. ]
    Motor Evoked Potentials at stimulus intensities ranging from 100-150% resting motor threshold, presented in random order.

  2. Motor Evoked Potential dose-response curve [ Time Frame: Baseline versus 16 hours following theta-burst stimulation. ]
    Motor Evoked Potentials at stimulus intensities ranging from 100-150% resting motor threshold, presented in random order.

  3. Motor Evoked Potential Amplitude Time Course [ Time Frame: 90 minutes following theta-burst stimulation. ]
    Change in the (electrical) amplitude of muscle responses to stimulation of the motor cortex will be recorded from the first dorsal interosseous muscle of the hand.


Other Outcome Measures:
  1. Safety outcomes [ Time Frame: Through study completion, on average 2 weeks. ]
    Adverse events will be tracked and recorded

  2. Side effects [ Time Frame: Pre-stimulus and 16 hours post-stimulus for both arms of the crossover study. ]
    Side effects will be tracked with the Toronto Side Effects Questionnaire


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

1. Healthy individuals 18-60 years of age.

Exclusion Criteria:

  1. Pregnancy
  2. Lactation
  3. Epilepsy
  4. Previous Stroke
  5. Current Renal Disease
  6. Current Liver Disease
  7. Current Alcohol Use Disorder
  8. Inability to refrain from alcohol use for 24 hours prior to each session and following each session.
  9. Allergy to antibiotics
  10. Use of isoniazid, ethionamide or bupropion
  11. Current psychiatric concerns
  12. History of bipolar disorder
  13. Family history of bipolar disorder
  14. Intracranial implants (dental implants are not an exclusion criteria)
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03432689


Locations
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Canada, Alberta
University of Calgary
Calgary, Alberta, Canada, T2N1N4
Sponsors and Collaborators
University of Calgary
Investigators
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Principal Investigator: Alexander McGirr, MD MSc University of Calgary
More Information
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Responsible Party: Alexander McGirr, Assistant Professor, University of Calgary
ClinicalTrials.gov Identifier: NCT03432689    
Other Study ID Numbers: REB17-2314
First Posted: February 14, 2018    Key Record Dates
Last Update Posted: November 9, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: There will be no sharing of individual participant data.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Cycloserine
Anti-Infective Agents, Urinary
Anti-Infective Agents
Renal Agents
Antibiotics, Antitubercular
 Antitubercular Agents
Anti-Bacterial Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action